3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.7. Neuromuscular blocking drugs
                      3.1.3.7.2. Non-depolarising NMBDs
                          3.1.3.7.2.3. Short-acting nondepolarising NMBDs
 3.1.3.7.2.3.1. Mivacurium 

Mivacurium

[SH4:p242-p245]

Quick summary

 

 

Usage

  • Short-acting nondepolarising NMBD

Structure

Structure

  • Benzylisoquinolinium nondepolarising NMBDs

Structure-activity relationship

  • Consists of 3 stereoisomers
    * Trans-trans, cis-trans, and cis-cis
  • Trans-trans and cis-trans are two most active and equipotent
    --> Accounts for 92-96% of mivacurium chloride
  • Cis-cis is only 1/10 the potency of the other two

Pharmacodynamics

Effects by systems

Muscle relaxation

  • Mivacurium produce maximum single-twitch depression
    * Orbicularis oculi BEFORE adductor pollicis
  • Suxamethonium produce maximum single-twitch depression at orbicularis oculi and adductor pollicis simultaneously
  • Recovery occurs at orbicularis oculi before adductor pollicis
    * For both mivacurium and suxamethonium

NB:

  • Muscle relaxation at orbicularis oculi correlates with paralysis of laryngeal adductor muscles and diaphragm

CVS

  • CVS response is minimal for doses up to 2 x ED95 (i.e. 0.15 mg/kg)
  • Doses of 3 x ED95 (0.20 mg/kg)
    --> Histamine release
    --> Decreased MAP (maximal within 1-3 minutes, lasting 1-3 minutes)

Pharmacokinetics (PK)

Absorption

IV

Metabolism

  • Trans-trans and cis-trans isomers are hydrolysed by plasma cholinesterase
    * At a rate 88% that of suxamethonium (i.e. still very fast)
    --> Responsible for the short duration of action
  • Cis-cis isomer is hydrolysed slowly, NOT by plasma cholinesterase
    --> Instead is cleared at a rate closer to intermediate-acting NMBDs

Metabolites

  • Metabolites from hydrolysis include
    * Quaternary amino alcohols
    * Quaternary monoesters
    --> Both inactive at NMJ

Rate of metabolism

  • Rate of hydrolysis by plasma cholinesterase depends on the plasma concentration of mivacurium
    --> The greater the concentration, the greater the rate of hydrolysis
  • Increasing the dose has only a small impact on the duration of action
    * Unlike other nondepolarising NMBDs
  • Recovery after infusion is
    * Independent of infusion duration
    * Comparable to recovery after single doses [PI]
  • Duration of action is increased in patients with atypical plasma cholinesterase

Elimination

  • 7% of mivacurium is excreted unchanged in urine
    --> Renal excretion is a minor pathway for clearance

Action profile

[SH4:p212,p242]

  • Onset of action = 2 - 3 minutes
  • Duration of action = 12 - 20 minutes
    * >25% of control twitch height
  • Duration of action = 25 - 40
    * >0.9 in TOF ratio

Pharmaceutics

Presentation

  • 20mg in 10mLs (2mg/mL)

Composition

  • Active = Mivacurium chloride
  • Inactive = HCl (for adjusting pH)
  • No preservative added (Mivacron)
  • pH = 4.5 (3.5 - 6.5) [PI]

Storage

  • Store below 25 degrees Celcius

Clinical

Administration

  • ED95 = 0.08 mg/kg
    * Or 0.07mg/kg (0.06-0.09 mg/kg) [PI]
    * 0.10 mg/kg in children 2-12 years old [PI]
  • Initial dose = 0.15 mg/kg over 5 to 15 seconds
    --> Clinical effective NMJ blockade last for 15 - 20 minutes
    --> Recovery to 95% in 25 - 30 minutes
  • Maintenance dose = 0.10mg/kg
    --> Provide another 15 minutes of additional blockade
  • Infusion rate = 0.5 - 0.6 mg/kg/hour
    * Start when early evidence of recovery from initial bolus
    * Reduction up to 40% with isoflurane or enflurane

Contraindication/precautions

  • Contraindicated in patients known to be homozygous for the atypical plasma cholinesterase gene
  • Caution in patients with reactive airway disease (e.g.asthma)
    * Due to risk of bronchospasm secondary to histamine release

Interactions

Anticholinesterases

[SH4:p244]

  • Neostigmine profoundly decrease plasma cholinesterease activity
    --> Interference with normal rapid spontaneous recovery
  • But both neostigmine and edrophonium antagonise the effects of mivacurium
    * Edrophonium provides more rapid antagonism

Volatile anaesthetics

  • Isoflurane and enflurane [PI]
    * Reduce dosage requirement by up to 25%
    * Prolong duration of action

Special consideration

Malignant hyperthermia

  • Does not trigger MH

Paediatrics

  • Clearance of mivacurium is faster in younger patients
  • Faster onset, shorter duration and faster recovery [PI]
    * Maximum blockade in 2 minutes
  • Higher dosage requirement (ED95 = 0.10mg/kg) [PI]
  • Initial dose for paediatrics = 0.1-0.2 mg/kg is recommended [PI]

Elderly

  • Onset time, duration of action, and recovery rate may be extended by 20-30%

Renal dysfunction

  • Renal excretion is a minor clearance pathyway
  • Renal failure is often associated with decreased plasma cholinesterase activity
    --> But clinically the prolongation of action is insignificant
  • c.f. According to [PI]
    --> Clinically effective duration of blockade produced by mivacurium 0.15mg/kg is approximately 1.5 times longer in ESRF

Hepatic dysfunction

Liver disease is often associated with

  • Decreased plasma cholinesterase activity
    --> Prolonged duration
  • Increased ECF volume
    --> Increased Vd
    --> Less intense NMJ blockade
    --> Clinically patient may appear resistant
    * Also seen with pancuronium and atracurium

But otherwise onset of action is unchanged

According to [PI]
--> Clinically effective duration of blockade produced by mivacurium 0.15mg/kg is approximately 3 times longer in end-stage hepatic failure

Burns

  • Burn injury decreases plasma cholinesterase activity
  • Burn injury causes receptor-mediated resistance to effects of nondepolarising NMBDs
  • Overall, the two effects cancel out
    --> Dosage unchanged
    * c.f. For other nondepolarising NMBDs, a higher dose is required

Trivia

History

 

Others

Brand name: Mivacron